The present invention relates to methods for treating conditions in which up-regulation of GAGs would be therapeutically beneficial and more specifically for treating such conditions by inhibiting the renin-angiotensin system.
It is known that glycosaminoglycans (GAGs) are the most abundant heteropolysaccharides in the body. They are essentially long unbranched polysaccharides comprising a repeating disaccharide unit which in turn comprise one of two modified sugars N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc) and a uronic acid such as glucuronate or iduronate. GAGs are located primarily on the cell surface or in the extracellular matrix (ECM). Specific GAGs of physiological significance include hyaluronic acid, dermatan sulfate, chondroitin sulfate, heparin, heparan sulfate, and keratan sulfate.
The majority of GAGs in the body are linked to core proteins, forming proteoglycans (also referred to as mucopolysaccharides). The GAGs extend perpendicularly from the core in a brush-like, structure. The linkage of GAGs to the protein core involves a specific trisaccharide composed of two galactose residues and a xylose residue (GAG-GalGalXyl-O—CH2-protein).
The high negative charge associated with GAGs, as well as their extended conformation imparts high viscosity to the ECM. Due to the low compressibility of GAGs, their presence in joint synovial fluid is essential. At the same time, their rigidity provides structural integrity to cells and provides passageways between cells, allowing for cell migration.
Because of the many vital body functions performed by proteoglycans in general and GAGs in particular, a deficiency in their production or their rapid degradation is associated with a wide range of disorders. In addition, many disorders have been shown to benefit by an increase in GAGs.
Osteoarthritis is the most common form of arthritis affecting over 20 million people in the United States alone. The incidence of osteoarthritis increases with age. The disease involves progressive deterioration of articular cartilage with minimal inflammation [Schoenherr et al. in Small Animal Clinical Nutrition 4.sup.th Ed., Hand et al. Eds., Walsworth Publishing Company, Marceline, Mo., 2000, 907-921; Hedbom et al., Cell Mol. Life. Sci 59:45-53, 2002; Pool, Front Biosci 4:D662-70, 1999].
Articular cartilage comprises chondrocytes (approximately 5%) and extracellular matrix (approximately 95%). The chondrocytes are important in the control of matrix turnover through production of collagen, proteoglycans and GAGs and enzymes for cartilage metabolism. The functional integrity of articular cartilage is determined by a balance between chondrocyte biosynthesis of extracellular matrix and its degradation.
Chondroitin sulfate is the predominant GAG found in articular cartilage. Together with its associated core protein, chondroitin sulfate has been shown to be reduced in various forms of arthritis including osteoarthritis as well as rheumatoid arthritis, leading to a decrease in cartilage thickness and stiffness [Altman R D, et al., Arthritis Rheum 16:179, 1973; Jasin H E, Dingle J T, J Clin Invest 68:571-581, 1981].
Standard drug therapy for the treatment of arthritis suppresses pain and inflammation, primarily through the use of non steroidal anti-inflammatory drugs (NSAIDS). However, these drugs also promote progression of the disease process by inhibiting GAG synthesis and cartilage repair. Therefore several attempts have been made to affect GAG and proteoglycan constituents of articular cartilage directly, using various approaches.
One such approach is the administration of glucosamine sulfate which is an essential component in GAG synthesis. Several human studies have shown a modest decrease in symptoms of osteoarthritis with the administration of glucosamine sulfate using oral or intraarticular injections [Reichelt A et al., Arzneimittelforschung 44:75-80, 1994; Reginster J Y, et al., Lancet 357:251-256, 2001; Vajaradul Y, Clin Ther 3:336-343, 1981]. A meta-analysis of the six best-designed trials found a small to moderate beneficial effect of glucosamine on pain [McAlindon T E, JAMA 15:1469-1675, 2000].
Another approach is the administration of chondroitin sulfate. A meta-analysis in 2003 evaluated eight trials that involved 755 patients with osteoarthritis of the knee who were assigned to receive chondroitin sulfate or placebo [Richy F, Arch Intern Med 163:1514-1522, 2003]. In terms of benefit, the likelihood of responding to chondroitin sulfate was significantly increased compared to placebo. However, there is limited information about the long-term effects of these supplements and their potential interactions. In addition, chondroitin and glucosamine usually require administration for many months before any benefit is felt.
Several genetically inherited diseases, for example the lysosomal storage diseases, result from defects in the lysosomal enzymes responsible for the metabolism of complex membrane-associated GAGs. These specific diseases, termed mucopolysaccharidoses (MPS) in reference to the earlier term, mucopolysaccharide, used for glycosaminoglycans, lead to an accumulation of defective GAGs within cells that fail to be secreted or degraded. There are at least 14 known types of lysosomal storage diseases that affect GAG metabolism; some of the more commonly encountered examples are Hurler's syndrome, Hunter's syndrome, Sanfilippo syndrome, Maroteaux-Lamy syndrome and Morquio's syndrome. All of these disorders, except for Hunter's syndrome, are inherited in an autosomal recessive manner.
Several approaches are being used or pursued for the treatment of MPS, most of which focus on gene therapy or enzyme replacement therapy for use alone in disease management. Additionally, researchers have identified a number of small molecules for the management of MPS. However, none of these approaches have shown full therapeutic efficacy.
Cystic fibrosis is another example of a disease which is associated with an increase in GAGs. Cystic fibrosis (CF) patients develop chronic lung infections associated with airway obstruction by viscous and insoluble mucus secretions. Chondroitin sulfate proteoglycans (CSPG) have been shown to contribute to the insolubility of CF sputum and treatment with chondroitinase was shown to ameliorate this effect [Khatri et al., Pediatr Res. 2003 April; 53(4):619-27].
There is thus a widely recognized need for, and it would be highly advantageous to have, novel therapeutic modalities for treating disorders associated with an under- or over-production of GAGs, which are devoid of the above limitations.
Angiotensin converting enzyme (ACE) is a metallopeptidase that participates in tissue regulatory peptide systems involving angiotensin II (All) and bradykinin. ACE catalyses the formation of All from its inactive precursor, angiotensin I, which itself is generated by cleavage of angiotensinogen by the protease renin. All exerts its biologic effects via specific, cell surface receptors, of which two major subtypes, named AT1 and AT2 receptors have been identified in humans. All is a potent vasoconstrictor, and can stimulate angiogenesis, fibroblast proliferation, and growth factor expression, each mediated by AT1 receptors [Timmermans P B, Pharmacol Review, 45:205-251, 1993]. Furthermore, ACE inhibitors (ACE-I) and AT1 receptor antagonists (ARB) inhibit these effects.
ACE inhibitors and ARBs are typically prescribed for the management of heart failure, hypertension and myocardial infarction. They are also considered as the standard of care for preserving renal function in chronic renal disease and in renal disorders associated with proteinuria. The precise mechanism of renoprotection associated with these agents is still not defined.
While researching the mechanism involved in the therapeutic effect ACE inhibitors and ARBs have on the pathogenesis of proteinuria, the present inventors unexpectedly discovered that inhibition of the renin-angiotensin system up-regulates GAGs. Thus, the use of ACE inhibitors and ARBs in the treatment of pathologies that would benefit from an up-regulation of GAGs is proposed herein. Particularly of interest is the local administration of such agents for the treatment of diseases associated with a low level of GAGs in the cartilage.
U.S. Pat. App. No. 20030078190 teaches the treatment of a wide range of disorders including rheumatoid arthritis (RA) and lupus erythematosus using ARBs optionally in combination with ACE-I inhibitors.
U.S. Pat. App. No. 20030040509 relates to the use of ACE inhibitors for the treatment of diseases associated with a reduced level of Angiotensin II. Included in their list of diseases are also those that are associated with a low level of GAGs.
Contrary to the present invention, both of these patent applications do not teach local administration of the renin-angiotensin modulating agent. Furthermore, therapeutic efficacy was shown only for cardiovascular disorders such as hypertension chronic heart failure and renal disorders such as proteinuria and chronic renal disease and not for cartilage, skin or lysosomal storage disorders.
There have been several small open-labelled trials of ACE inhibitors in patients with rheumatoid arthritis, with variable results [Martin M F et al., Lancet 1984; 1:1325-8; Bird H A et al., J. Rheumatol 1990; 17:603-8] using the ACE inhibitor captopril. The clinical benefits of captopril were attributed to structural similarities with penicillamine due to its thiol residue [Martin M F et al., Lancet 1984; 1: 1325-8]. In a later study ACE-I quinapril was shown to suppress inflammatory arthritis in mice [Dalbeth et al., Rheumatology 44:24-31, 2004]. The ARB candesartan had a similar inhibitory effect on disease activity as well. In all these studies, local administration of the renin angiotensin system inhibitors was not suggested and the effect of these agents on GAGs was not postulated.